Development of targeted therapy for advanced non-small cell lung cancer with rare driver oncogenes as RET or MET

Targeted therapy based on driver oncogenes such as EGFR, ALK, or ROS1 has become standard of care in patients with advanced non-small cell lung cancer (NSCLC). However, the incidence of each oncogenic driver mutation is very low except for EGFR mutations in East-Asian patients. Large scale screening systems are clearly needed for the development of targeted therapy for NSCLC patients with rare driver oncogenes. A nationwide lung cancer genomic screening project in Japan, so called LC-SCRUM-Japan has been operated since February 2013. In 2012, RET rearrangements were identified as new oncogenic driver mutations occurring in 1% to 2% of patients with NSCLC. Several phase 2 trials to evaluate single-agent multi-targeted RET inhibitors including cabozantinib, vandetanib, or lenvatinib, have demonstrated clinical antitumor activity in patients with RET-rearranged NSCLC. However, this efficacy was lower than that of targeted therapy in NSCLC patients harboring sensitizing EGFR mutations, ALK or ROS1 rearrangements. Development of highly selective RET inhibitors might help to have greater antitumor activity. More recent investigations focusing on MET exon 14 skipping mutation or MET high amplifications have been notable for meaningful clinical responses to MET inhibitor in patients with MET-mutated NSCLC. Such targetable MET gene alterations are also rare occurrence in NSCLC. Several clinical trials to evaluate MET inhibitors such as crizotinib, tepotinib, or capmatinib are ongoing in patients with MET-mutated NSCLC. RET rearrangement and MET exon 14 skipping mutation are new molecular subgroup of NSCLC suitable for targeted therapy. Patients with NSCLC harboring rare driver oncogenes as RET or MET will derive more effective benefit from specific targeted therapy.